No abstract

A prospective study of 31 chronically hemodialyzed patients was made to investigate the incidence and pathology of pulmonary calcification and the relation of the latter to ventilatory function. Fifteen of the patients have died thus far; 9 had evidence of lung calcification. The lesions occurred predominately in alveolar septa and were associated with varying degrees of fibrosis and alveolar septal thickening. Only one patient had X-ray evidence of calcification. An X-ray diffraction analysis showed a predominant pattern of whitlockite (CaMg)3(Po4)2 in deposits. Patients with the severest pulmonary calcification had abnormalities of vital capacity, carbon monoxide diffusion, and Po2. Serum calcium levels were slightly higher in patients with calcification, but there was no measurable association with the duration of dialysis, serum phosphorus, calcium X phosphorus product, magnesium, bicarbonate, or arterial pH. These data show that pulmonary calcification occurs with high frequency in patients undergoing long-term hemodialysis and that such lesions are associated with restrictive and diffusion ventilatory defects.

We sought to determine the importance of calcium phosphate deposition in the functional deterioration of damaged or diseased kidneys. Using the remnant-kidney model in rats, we found that dietary phosphate restriction prevented proteinuria, renal calcification, histologic changes, functional deterioration and death in uremia. Histologic examination of the remnant kidney in the nonrestricted animals showed calcium and phosphorus deposits in the cortical tubular cells, basement membranes and interstitium. A similar degree and pattern of calcification have been found in preliminary studies of human end-stage kidneys. Our results suggest that the calcification produced by the altered phosphorus metabolism present in the uremic state incites an inflammatory and fibrotic reaction leading to destruction of the remnant kidney. Phosphate restriction prevents this response in the remnant kidney. The potential applicability of these findings to other forms of experimental renal disease and to clinical uremia remains to be explored.

The secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 (1,25D) has been shown to regulate the growth and differentiation of human prostate cancer (PCa) cells, although the precise molecular mechanisms mediating these effects have not been defined. Previous studies in our laboratory demonstrated that the antiproliferative effects of 1,25D on PCa cells are mediated through the nuclear vitamin D receptor (VDR). In the present study, we performed gene profiling of LNCaP human PCa cells following 1,25D treatment and identified the antitumorigenic gene, prostate derived factor (PDF), as being highly induced by 1,25D. PDF is a member of the TGF-beta superfamily and has been implicated in a variety of functions directly related totumorigenicity including antiproliferative and pro-apoptotic effects. Gene expression studies using 1,25D analogs and a VDR antagonist demonstrate that 1,25D-mediated induction of PDF message and protein in PCa cells is dependent on VDR action. PDF is a transcriptional target of the tumor suppressor, p53. Here we show that the expression of PDF in nine PCa cell lines is dependent on functional p53. Additionally, transfection of p53-null ALVA-31 PCa cells with a p53 expression plasmid, and expression of dominant negative p53 in LNCaP PCa cells, show that the ability of VDR to induce PDF requires functional p53. Importantly, forced PDF expression in PC-3 cells results in decreased cell proliferation, soft agar cloning, and xenograft tumor size. These data demonstrate that PDF exerts antitumorigenic properties on PCa cells and its regulation by 1,25D may provide insights into the action of 1,25D in PCa.